This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. I. HYPOTHESIS Our Study Hypothesis: A major purpose of this study is to confirm that chimeric Epstein-Barr Virus specific Cytotoxic T Lymphocytes (EBV CTL) expressing a Chimeric Antigen Receptor recognizing CD19 (CD19CAR) will have equal or superior survival to activated Peripheral Blood T cells (PBTL) expressing a CD19CAR that also incorporates the CD28 co-stimulatory endodomain. There is considerable evidence to support this hypothesis. First, clinical studies of more than 70 recipients of CTL have shown that both CD4+ and CD8+ EBV specific T cells persist in activated form and recirculate. Second, our gene-marking studies have shown that these circulating EBV-specific T cells will respond both in vivo and ex vivo to viral antigen challenge, by marked proliferation and increased activation, even when this challenge occurs 6 years or more from the date of infusion. Finally, multiple animal studies have shown that the continued presentation of antigens associated with class I and class II MHC molecules on effective antigen presenting cells is critical to establish and maintain T cell memory, since it is only in this way that cognate interactions can occur between CD4+ and CD8+ effector cells. T cells generated in this way will persist and readily recapitulate an immune response on antigenic challenge. To fully test this hypothesis we plan to compare the persistence and activity of CD19CAR-bearing EBV-CTLs to peripheral blood T-cells co-expressing a CD19CAR and a co-stimulatory CD28-endodomain, given to patients with relapsed/refractory intermediate or low-grade non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (B-CLL). Both cell types will express identical chimeric receptors but the presence or absence of CD28 endodomains will allow differential tracking by real-time PCR. Each patient will receive the same dose of T cells (EBV-CTLs and PBTLs) transduced with each of the vectors, i.e., each patient will receive both cell populations. II. SPECIFIC AIMS PRIMARY OBJECTIVE: To evaluate the safety of escalating doses of autologous PBTLs and EBV-CTLs, both genetically modified to express artificial T-cell receptors targeting the CD19 molecule (CD19CAR), in patients with refractory/relapsed low and intermediate-grade NHL and B-CLL. SECONDARY OBJECTIVES: To measure the differential survival and function of CD19CAR transduced PBTLs and EBV-CTLs in vivo, in particular to determine if CD19CAR transduced EBV-CTLs survive longer than CD19CAR-CD28 transduced PBTLs. To measure the anti-tumor effects of CD19CAR transduced T- lymphocytes in patients with low and intermediate-grade NHL or B-CLL.